Postmortem findings in a case of variant Creutzfeldt-Jakob disease treated with intraventricular pentosan polysulfate.

BACKGROUND: A small number of patients with variant Creutzfeldt-Jakob disease (vCJD) have been treated with intraventicular pentosan polysulfate (iPPS) and extended survival has been reported in some cases. To date, there have been no reports on the findings of postmortem examination of the brain in treated patients and the reasons for the extended survival are uncertain. We report on the neuropathological findings in a case of vCJD treated with PPS. METHODS: Data on survival in vCJD is available from information held at the National CJD Research and Surveillance Unit and includes the duration of illness in 176 cases of vCJD, five of which were treated with iPPS. One of these individuals, who received iPPS for 8 years and lived for 105 months, underwent postmortem examination, including neuropathological examination of the brain. RESULTS: The mean survival in vCJD is 17 months, with 40 months the maximum survival in patients not treated with PPS. In the 5 patients treated with PPS survival was 16 months, 45 months, 84 months, 105 months and 114 months. The patient who survived 105 months underwent postmortem examination which confirmed the diagnosis of vCJD and showed severe, but typical, changes, including neuronal loss, astrocytic gliosis and extensive prion protein (PrP) deposition in the brain. The patient was also given PPS for a short period by peripheral infusion and there was limited PrP immunostaining in lymphoreticular tissues such as spleen and appendix. CONCLUSIONS: Treatment with iPPS did not reduce the overall neuropathological changes in the brain. The reduced peripheral immunostaining for PrP may reflect atrophy of these tissues in relation to chronic illness rather than a treatment effect. The reason for the long survival in patients treated with iPPS is unclear, but a treatment effect on the disease process cannot be excluded.

Diagnosing variant Creutzfeldt-Jakob disease: a retrospective analysis of the first 150 cases in the UK.

INTRODUCTION: Establishing an early clinical diagnosis in variant Creutzfeldt-Jakob disease (vCJD) can be difficult, resulting in extended periods of uncertainty for many families and sometimes a view that patients have been subjected to unnecessary investigations. This issue is accentuated by the progressive nature of vCJD and by the difficulty in achieving a confident clinical diagnosis before an advanced stage of illness. Although diagnostic delay may be a result of the non-specific early clinical features, a systematic analysis of the process of diagnosis was undertaken, with the aim of trying to achieve earlier diagnosis of vCJD. METHODS: Retrospective case file analysis was undertaken of the first 150 definite and clinically probable cases of vCJD identified by the UK surveillance system. RESULTS: There is a significant interval between illness onset and presentation to a primary care physician, which is influenced by the nature of the initial clinical features. Neurological review is invariably sought following the development of clinical signs and a diagnosis is then established relatively quickly. Despite the progressive clinical course, a confident clinical diagnosis is not usually achieved until a relatively advanced stage of illness (mean time to diagnosis 10.5 months) with a more rapid clinical progression accounting for those cases diagnosed earlier after symptom onset. CONCLUSIONS: Early clinical diagnosis in vCJD is not possible in the great majority of cases because of non-specific initial symptoms. Once neurological signs develop, a diagnosis is usually made promptly but this is often at a relatively advanced stage of illness. The inherent delays in the diagnosis of vCJD have implications for those involved in both public health and therapeutics.

The role of cerebrospinal fluid 14-3-3 and other proteins in the diagnosis of sporadic Creutzfeldt-Jakob disease in the UK: a 10-year review.

BACKGROUND: It is 10 years since the detection of cerebrospinal fluid (CSF) 14-3-3 was included in the diagnostic criteria for sporadic Creutzfeldt-Jakob disease (sCJD) by the WHO. Since that time, other CSF proteins, such as S100b and tau protein, have been proposed as surrogate markers for sCJD. The authors aimed to investigate the diagnostic value of each of these three proteins. METHODS: CSF samples collected from patients who were referred to the National CJD Surveillance Unit as suspected cases of sCJD during the period 1997-2007 were analysed for 14-3-3, S100b and tau protein. The sensitivity, specificity, positive predictive value and negative predictive value of each of these markers, either alone or in combination for the diagnosis of sCJD, were assessed. The impact of CSF 14-3-3 analysis on the case classification of sCJD was investigated. RESULTS AND DISCUSSION: CSF 14-3-3 had the greatest sensitivity (86%) when compared with tau protein (81%) and S100b (65%). The combination of a positive CSF 14-3-3 or an elevated tau protein with a raised S100b had the highest positive predictive power for sCJD. During the study period, 100 patients were classified as probable sCJD solely on the basis of the clinical features and a positive CSF 14-3-3. The most sensitive marker for sCJD was a positive CSF 14-3-3. The analysis of CSF 14-3-3 plays a crucial role in the case classification of sCJD.

Variant Creutzfeldt-Jakob disease and exposure to fractionated plasma products.

BACKGROUND: The risk to public health of onward transmission of variant Creutzfeldt-Jakob disease (vCJD) via blood transfusion and plasma product administration is of on-going concern, particularly with the recent reported detection of abnormal prion protein in a person with haemophilia. OBJECTIVES: To describe the history of fractionated plasma product exposure in clinical cases of vCJD in the UK. METHODS: Through examination of records held at the National CJD Surveillance Unit (from relatives, general practices and hospitals). RESULTS: Nine out of 168 UK vCJD cases had a history of receipt of fractionated plasma products on 12 different occasions (1 pre-vCJD risk in 1970, the remaining between 1989-1998). According to the UK CJD Incident Panel risk assessment criteria, 11 were low-risk products and one was low or medium risk. CONCLUSION: It is unlikely that any of the UK vCJD clinical cases to date were infected through exposure to fractionated plasma products. However, the possibility that such transmission may result in vCJD cases in the future cannot be excluded.

Sporadic Creutzfeldt-Jakob disease with cerebellar ataxia at onset in the UK.

OBJECTIVE: To determine the frequency, in the UK, of sporadic Creutzfeldt-Jakob Disease (sCJD) with a cerebellar ataxic onset, and to describe the clinical features of the syndrome. METHODS: A retrospective review of autopsy-proved cases of sCJD cases in the UK, 1990-2005, identifying those presenting with cerebellar features without early cognitive decline. RESULTS: 29 of 618 (5%) patients with sCJD had an isolated cerebellar onset. Mean illness duration was 9 months. Subsequently, 21 (72%) developed myoclonus and 23 (79%) developed pyramidal features. Magnetic resonance imaging showed high signal in the basal ganglia in 11 of 14 (79%) patients. 7 of 15 (47%) patients were valine homozygotic at prion protein gene (PRNP)-129. Only 8 (28%) cases were referred to the surveillance unit after death. CONCLUSION: A better definition of sCJD presenting with an isolated cerebellar syndrome might improve future case recognition and contribute to the determination of its cause.

Unsuccessful intraventricular pentosan polysulphate treatment of variant Creutzfeldt-Jakob disease.

Pentosan polysulphate, delivered by chronic intraventricular infusion, has been proposed as a potential therapy for human prion disease. The first treated patient is still alive several years after treatment started. Here we describe in detail a case of variant Creutzfeldt-Jakob disease in which this treatment was started at a relatively early stage but had no definite clinical benefit. The patient died from disease progression 16 months after diagnosis and 5 months after pentosan polysulphate treatment was commenced.

Dura mater-associated Creutzfeldt-Jakob disease: experience from surveillance in the UK.

Between 1970 and 2003, seven cases of human dura mater-associated Creutzfeldt-Jakob disease (CJD) were identified in the UK. Furthermore, we identified a case of CJD in a porcine dura graft recipient. The mean incubation period of the human dura mater cases was 93 (range 45-177) months. The clinico-pathological features of the cases are described and compared with cases previously reported in the world literature.

Raised CSF phospho-tau concentrations in variant Creutzfeldt-Jakob disease: diagnostic and pathological implications.

OBJECTIVE: To investigate whether phosphorylated tau protein (tau-pT181) is increased in variant Creutzfeldt-Jakob disease (vCJD) and if the tau-pT181/tau protein ratio is useful for distinguishing between patients with and without CJD. METHODS: CSF tau protein and tau-pT181 were measured in 50 patients with sporadic CJD (sCJD), 51 patients with vCJD, 46 sCJD controls, and 37 vCJD controls, using Innotest hTau and Innotest P-Thr181, Innogenetics. RESULTS: Concentrations of CSF tau protein were increased in sCJD (5120 v 367 pg/ml in controls, p < 0.001) and vCJD (952 v 106 pg/ml, p < 0.001); tau-pT181 was also raised in sCJD (61 v 35 pg/ml in controls, p = 0.002) and vCJD (114 v 33 pg/ml, p < 0.001). Median concentrations of tau-pT181 were higher in vCJD than in sCJD (p < 0.001). The tau-pT181/tau protein ratio was lower than in controls in both sCJD (12 v 128 (p < 0.001)) and vCJD (119 v 279 (p < 0.001)). Mean tau-pT181/tau protein ratio was 10-fold higher in vCJD than in sCJD. Raised CSF tau protein had the highest efficiency for distinguishing sCJD and vCJD from controls. CONCLUSIONS: CSF tau-pT181 concentrations are raised in vCJD and are higher than in sCJD. Measurement of CSF tau-pT181/tau protein ratio does not improve the diagnostic efficiency of CSF tau protein alone for either vCJD or sCJD. The higher concentration of CSF tau-pT181 found in vCJD suggests that unexplained pathogenic factors influence the phosphorylation of tau protein in vCJD patients.

Isolated visual symptoms at onset in sporadic Creutzfeldt-Jakob disease: the clinical phenotype of the "Heidenhain variant".

BACKGROUND: The Heidenhain variant of sporadic Creutzfeldt-Jakob disease (sCJD) is commonly understood to represent cases with early, prominent visual complaints. The term is clarified to represent those who present with isolated visual symptoms. This group may pose diagnostic difficulties and often present to ophthalmologists where they may undergo needless invasive procedures. METHOD: A retrospective review of 594 pathologically proved sCJD cases referred to the UK National CJD Surveillance Unit over a 15 year period to identify Heidenhain cases. RESULTS: 22 cases had isolated visual symptoms at onset with a mean illness duration of 4 months. The mean age at disease onset was 67 years. Most displayed myoclonus, pyramidal signs, and a delay in the onset of dementia for some weeks. 17 (77%) were referred initially to ophthalmology. Two underwent cataract extraction before diagnosis. All tested cases were homozygous for methionine at codon 129 of the prion protein gene. CONCLUSIONS: This rare, but clinically distinct, group of patients with sCJD may cause diagnostic difficulties. Because ocular intervention carries with it the risk of onward transmission awareness of this condition among ophthalmologists is important.

A case-control study of sporadic Creutzfeldt-Jakob disease in the United Kingdom: analysis of clustering.

BACKGROUND: The authors investigated whether cases of sporadic Creutzfeldt-Jakob disease (CJD) had lived closer to one another at some time in life than individuals without sporadic CJD. Such a phenomenon would be compatible with some cases resulting from transmission. METHODS: UK sporadic CJD cases occurring from 1990 to 1998 were identified. Age-, sex- and hospital-matched controls were recruited. Lifetime residential histories were obtained by interview, usually with a proxy respondent. With use of Monte Carlo simulation, the residential proximity of cases during various time periods was compared with that expected in the absence of any clustering, using the information collected on the controls. RESULTS: Two hundred twenty sporadic CJD disease cases and 220 controls were included. Cases lived closer together than might be expected in the absence of any disease-clustering mechanism. This evidence became stronger as the critical period during which residential proximity was required to have occurred extended further into the past. CONCLUSIONS: These findings are consistent with some sporadic Creutzfeldt-Jakob disease (CJD) cases resulting from exposure to a common external factor. The rarity of sporadic CJD suggests that repeated point-source outbreaks of infection are more likely to explain our observations than direct case-to-case transmission. Identifying sources of such outbreaks many years after the event will be extremely difficult.

Possible transmission of variant Creutzfeldt-Jakob disease by blood transfusion.

BACKGROUND: Variant Creutzfeldt-Jakob disease (vCJD) is a novel human prion disease caused by infection with the agent of bovine spongiform encephalopathy (BSE). Epidemiological evidence does not suggest that sporadic CJD is transmitted from person to person via blood transfusion, but this evidence may not apply to vCJD. We aimed to identify whether vCJD is transmissible through blood transfusion. METHODS: The national CJD surveillance unit reported all cases of probable or definite vCJD to the UK blood services, which searched for donation records at blood centres and hospitals. Information on named recipients and donors was provided to the surveillance unit to establish if any matches existed between recipients or donors and the database of cases of vCJD. Recipients were also flagged at the UK Office of National Statistics to establish date and cause of death. FINDINGS: 48 individuals were identified as having received a labile blood component from a total of 15 donors who later became vCJD cases and appeared on the surveillance unit's register. One of these recipients was identified as developing symptoms of vCJD 6.5 years after receiving a transfusion of red cells donated by an individual 3.5 years before the donor developed symptoms of vCJD. INTERPRETATION: Our findings raise the possibility that this infection was transfusion transmitted. Infection in the recipient could have been due to past dietary exposure to the BSE agent. However, the age of the patient was well beyond that of most vCJD cases, and the chance of observing a case of vCJD in a recipient in the absence of transfusion transmitted infection is about 1 in 15000 to 1 in 30000.

Deaths from variant Creutzfeldt-Jakob disease in the UK.

In 2002, 17 people died from variant CJD (vCJD) in the UK, compared with 20 in 2001 and 28 in 2000. We analysed data for deaths from vCJD since 1995 and estimated the underlying trend in mortality. The trend had a quadratic component (p=0.005), suggesting that the increase was not exponential, and that the previously increasing trend is slowing down. The death rate peaked in 2000. These findings are encouraging, but mortality might increase again in the future.